Pharmacology Flashcards
1
Q
what 2 endogenous substance act on the B1-adrenoceptors in the heart?
A
noradrenaline (sympathetic transmitter)
adrenaline (hormone)
2
Q
what G protein do B1-adrenoceptors in the heart couple to?
A
Gs proteins
3
Q
when a B1-adrenoceptor is stimulated, what does the Gs coupled protein do?
A
acitvates adenylyl cyclase to increase intracellular cAMP concentration stimulates pKA (within myocytes)
4
Q
what does increasing intracellular cAMP concentration within the pacemaker cells do?
A
increases slope of pacemaker potential and so increases heart rate
(positive chronotrophic effect)
5
Q
what endogenous substance acts on M2 muscarinic cholinoreceptors in the heart?
A
ACh
6
Q
What G protein do M2-adrenoceptors in the heart couple to?
A
Gi
7
Q
when a M2 muscarinic receptor is stimulated, what does the Gi coupled protein do?
A
- decreases activity of adenylyl cyclase to decrease intracellular concentrations of cAMP
- opens potassium channels to cause hyperpolarisation of SA node
8
Q
what does decreasing intracellular concentrations of cAMP and opening potassium channels within pacemaker cells do?
A
decreases slope of pacemaker potential and so decreases heart rate
(negative chronotropic effect)
9
Q
what are the 3 internodal pathways between the SA node and the AV node? (contained within the right atrium)
A
anterior internodal pathway
middle internodal pathway
poterior internodal pathway
10
Q
what is pathway goes to the left atrium from the SA node?
apart from cell-cell spread of excitation through gap junctions
A
anterior interatrial myocardial band
Bachmann’s Bundle
11
Q
what does the bundle of his split up into?
A
right bundle branch
left bundle branch (which splits into anterior division and posterior division)
12
Q
what is the hierarchy of pacemakers?
A
SA > AV > other cells within the heart
13
Q
why is it necessary that the AV node can produce an AP?
A
in case the SA node fails
14
Q
why is it necessary that other cells within the heart can produce an AP? (ie like within the conducting fibres)
A
in case both the SA and AV nodes fail
15
Q
what is the inwards current of the pacemaker potential also known as?
A
I(f)
funny current
16
Q
what stimulates the inwards current of the pacemaker potential? (funny current)
A
- hyperpolarisation
(ie turning resting potential negative) - cAMP
17
Q
what does blocking HCN (hyperpolarisation-activated cycline neucleotide gated) channels do to the pacemaker potential slope?
A
decreases the slope
negative chronotrophic effect
18
Q
what does ivabradine do?
A
a selective blocker of HCN channels so slows the heart rate down
19
Q
what medical condition is ivabradine used in and why?
A
angina
because slower rate reduces O2 consumption and so reduces coronary artery supply requirement
20
Q
what does isoprenaline do?
A
a agonist of B-adrenoceptors and so increases intracellular cAMP concentration and so increases heart rate
21
Q
what do thyroid hormones do to heart rate?
A
increase heart rate
positive chronotrophic effect
22
Q
what does adenosine do to the heart rate?
A
decreases heart rate
negative chronotropic effect
23
Q
what does nitric oxide do to the heart rate?
A
increases heart rate
positive chronotrophic effect
24
Q
what are the 6 effects of the sympathetic system on the heart?
A
- increases heart rate
- increases contractility
- increases conduction velocity in AV node (decreases delay)
- increases automacity (tendancy for non-nodal regions to acquire spontaneous activity)
- decreases duration of systole
- decreases cardiac efficiency (with respect to O2 consumption)
25
what are the 4 effects of the parasympathetic system on the heart?
1. decreased heart rate
2. decreased contractibility
3. decreased conduction in AV node (increased delay)
4. overaction may cause dysrhythmias in the atria (not fatal)
26
what is the Frank-Starling mechanism?
the more the myocardium is stretched, the greater force it exerts upon contraction
(despite of autonomic control)
[ie the greater the venous return, the greater the stroke volume]
27
what autonomic control can tweak the frank-starling curve?
sympathetic
28
what happens to the frank-starling curve in cardiac failure?
curve fails as force is not able to match the venous return (stretch)
29
what 3 factors contribute to increased venous return? (and therefore increased stretch)
1. increased skeletal muscle activity
2. adrenergic effects on blood vessels (increased venous tone)
3. respiratory pump (increased depth and freq)
30
what does increased intracellular calcium cause?
contraction
31
what is excitation coupling?
coupling mechanical force to electrical excitation
32
for the action potential to excite a ventricular muscle cell what must it do when it sweeps across the cell?
dive down into the T-tubules
33
during depolarisation of a ventricular muscle cell (fast Na influx) what happens?
voltage-gated L-type Ca channels located in the T tubule membrane are opened by depolarisation and let a small amount of Ca in
34
what does the small calcium influx within a ventricular muscle cell cause?
the activation of RyR (ryanodine) receptors which cause the release of large amounts intracellular calcium from the SR.
35
what is the process called by which RyR receptors in the ventricular muscle are stimulated cause the release of calcium from the SR?
Ca-induced Ca release
36
for contraction within the ventricular muscle cell to occur what does calcium activate?
the myofilaments
37
once the myofilaments within the muscle cell have been activated what occurs?
the Ca is removed from the cytoplasm by the SR CA ATPase (SERCA) and the sarcolemma Na/Ca exchanger
38
what does the decreased intracellular concentration of calcium after myofilament activation cause?
relaxation
39
what do positive chronotropic drugs/hormones do to the calcium transients within the cardiac myocyte?
cause bigger and faster calcium transients
40
what is the function of the RyR within the myocyte?
when stimulated by calcium cause the Ca-induced Ca release from SR
41
what is the function of SERCA 2a within the myocyte?
removal of Ca at the end of a beat (puts Ca++ back into stores
42
what are the 4 sites of protein kinase A action within the myocyte?
RyR (ryanodine receptor)
LTCC (L-type calcium channels on T-tubule membrane)
PLB
Troponin
43
what does protein kinase A phosphrylation of LTCC cause within the myocyte?
increases trigger calcium and so increases Ca-induced Ca release (causing increased force of contraction)
44
what does protein kinase A phosphorylation of RyR do within the myocyte?
increases size of Calcium transient (ie amount leaving SR) and therefore increases force of contraction
45
what does protein kinase A phosphorylation of PLB do?
increases uptake by SERCA and so:
1. accelerates relaxation (makes contraction shorter)
2. increases SR calcium content
46
what is the function of troponin?
regulates the actin/myosin interaction using calcium
47
what does protein kinase A phosphorlation of troponin do?
phosphorylation of troponin reduces the affinity for calcium, there is a minor reduction in contraction but this accelerates relaxation
48
what is the principal determinant of calcium binding to troponin C to cause contraction?
the rate calcium diffuses from the SR
| ie phosphorylation of RyR
49
what is the principle determinant of the unbinding of calcium once a contraction has occured?
phosphorylation of troponin
50
what is dobutamines effect on the heart?
selective b1-adrenoceptor agonist so increases force and rate
51
when is exogenous adrenaline used?
during cardiac arrest
emergency treatment of asthma
anaphylactic shock
52
when is dobutamine used?
for acute, but potentially reversible, heart failure
| eg following cardiac surgery
53
why are b-1 adrenoceptor agonists regarded as 'toxic'?
because long term stimulation of sympathetic system causes heart failure
54
what is propanolol?
a non-selective b-blocker
| antagonist of b1 and b2 adrenoceptors
55
at rest, what is the effect of b-adrenoceptor antagonists on the heart and why?
little effect on rate, force
| this is due to the sympathetic system not being too active during rest
56
during exercise, what is the effect of b-adrenoceptor antagonists on the heart?
rate and force are significantly depressed
coronary vessel diameter are marginally vasodilated
(as myocardial O2 requirement falls there is more effective oxygenation of the heart)
57
what do b2-adrenoceptors stimulation cause on the coronary vessels?
vasodilation
58
what is atenolol?
a selective B1-blocker
59
what is metoprolol?
a selective B1- blocker
60
what are the 4 clinical uses of B-adenoceptor antagonists?
1. dysrhythmias
2. hypertension
3. angina
4. heart failure
61
what are the 6 adverse effects of b-blockers?
| * which have a lesser risk is B1 selective agents are used
1. bronchospasm*
2. aggravation of cardiac failure
3. bradycardia (or heart block)
4. hypoglycaemia* (in patients with poorly controlled diabetes)
5. fatigue (due to decreased CO and skeletal muscle perfusion)
6. cold extremities (loss of vasodilation in cutaneous vessels)
62
why might b-blockers cause aggravation of cardiac failure?
patients with heart disease may rely on sympathetic drive to maintain an adequate CO for perfusion of their body tissues
63
what is atropine?
a non selective muscarinic receptor antagonist
64
what are the effects of atropine on the cardiovascular system?
1. increase in heart rate (modest in normal subjects, pronounced in athletes who have increased vagal tone)
2. no effect on TPR (no parasympathetic innervation to blood vessels)
3. no effect upon the respone to exercise
65
what are the 3 clinical uses of atropine?
1. to reverse bradycardia following an MI (in which vagal tone is elevated)
2. as an adjunt to anaesthesia
3. in anticholinesterase poisoning (to reduce excessive parasympathetic activity
66
what is the pharmocodynamic effect of digoxin?
increases contractility of the heart?
67
what type of drugs are digoxin and dobutamine?
inotropic drugs
| enhance contractility
68
what is the clinical use of digoxin?
in heart failure
| especially in patients with AF- due to effects on AV node
69
how does digoxin work?
1. blocks the sarcolemma Na/K ATpase which results in calcium unable to leave cell causing more to go into the SR
(incresed contactility)
2. increases AV node refractory period
70
what effect does digoxin have on the autonomic system?
none
71
what happens if you give digoxin to a patient with hypokalaemia?
effects of digoxin are dangerously enhanced
72
what are the 2 most serious effects of digoxin?
1. excessive depression of AV node conduction- heart block
| 2. dysrhythmias
73
what is levosimendan?
a calcium-sensitiser: inotropic drug
74
how does levosimendan work?
1. binds to troponin C in cardiac muscle sensitising it to the action of calcium
2. causes vasodlation
75
what is the clinical use on levodimendan?
treatment of acute decompensated heart failure
76
what does contraction of vascular smooth muscle depend on?
intracellular concetration of calcium
77
in a vascular smooth muscle cell what are the 2 ways calcium concentration can be increased?
influx of Ca across membrane gradient (conc or electrical gradient)
Ca released from intracellular stores (eg SR)
78
in smooth muscle cell (very different to cardiac and skeletal muscle), how does calcium cause contraction?
1. calcium binds to calmodulin to form a calcium-camodulin complex.
2. this complex activates myosin light chain kinase (MLCK) which phosphorylates myosin-light chain.
3. the phosphorylated myosin-LK can form cross bridges and allow myosin and actin to slide over each other and contract.
79
how does relaxation occur in a vascular smooth muscle cell?
1. cGMP activates myosin-LC-phosphotase
2. myosin-LC-phosphotase strips a phosphate from the phosphorylated myosin-LC converting it into inactive myosin-LC.
3. the cross bridges break and relaxation occur
80
compare the functions of MLCK and MLC-phosphotase
MLCK phosphorylates inactive Myosin-LC
MLC-phosphotase strips a phosphate from active mysoin-LC
reverse roles
81
what 3 vasodilating substances work through NO production?
bradykinin
ANP
serotonin (5-HT)
82
what type of manner does NO signal in?
paracrine (induces an effect in cells near by)
83
what does NO do within a vascular smooth muscle cell?
1. activation of guanylate cyclase
| 2. activates calcium-dependent potassium channels
84
what is the role of guanylate cyclase within a vascular smooth muscle cell?
(activated by NO)
converted GTP to cGMP
| cGMP initiates the relaxation pathway
85
what happens when calcium-dependent potassium channels are activated?
cause potassium to leave the cell causing repolarisation.
| this repolarisation closes voltage gated calcium channels and causes relaxation
86
what 2 ways can calcium-dependent potasssium channels become activated?
stimulation by NO
| depolarisation
87
what is the function of organic nitrates?
relax all type of smooth muscle
88
why are organic nitrates a first choice for angina patients?
1. they redirect the blood from unhealthy vessels to healthy vessels to bypass the block
2. decreased myocardial oxygen requirement
89
why is there a decreased myocardial oxygen requirement when using organic nitrates?
```
decreased preload (due to reduced venomotor tone)
decreased afterload (de to reduced vasomotor tone)
```
90
how do organic nitrates redirect blood from unhealthy vessels to bypass blockages?
dilate collateral vessels
91
why are arterioles downstream to a blockage already fully dilated?
due to local factors such as hypoxia etc
92
what are the 2 main types of organic nitrates used in practice?
glyceryltrinitrate
| isosorbide mononitrate
93
compare glyceryltrinitrate and isosorbide mononitrate in terms of length of acting?
GTN- short acting (30 min)
| isosorbide mononitrate- long acting (4 hours)
94
compare glyceryltrinitrate and isosorbide mononitrate in terms of effect of first pass metabolism?
GTN- extensive first pass metabolism
| isosorbide mononitrate- resistant to first pastt metabolism
95
how it GTN administered?
sublinguial tablet or spray or transdermal patch
96
how should organic nitrates be used for angina?
prophylactically
| GTN can also relieve attacks
97
what can happen with repeated administration of organic nitrates?
tolerance- diminished effect
98
how can you minimise tolerance of organic nitrates?
nitrate-low periods
| usually at night
99
what is a common effect of organic nitrates which may occur initially?
headaches due to dilation of cranial circulation
100
what 3 things down regulate the production of endothelin?
nitric oxide
natriuretic peptides
shear stress
101
what are bosentan and ambrisentan?
antagonists of the ETa receptor (which endothlin acts on)
102
when are bosentan and ambrisentan (antagonists of the ETa receptor) used?
in treatment of pulmonary hypertension
103
what is a long term effect of angiotensin II?
promotes cell growth
104
what are the 2 functions of ACE?
converts angiotensin I to angiotensin II
| inactivated bradykinin
105
where is ACE found?
bound to the membrane of endothelial cells
106
what is the role of ace inhibitors?
| -pril
block the conversion of angiotensin I to angiotensin II
107
compare the effect of ACE inhibitors in normal subjecs and hypertensive patients?
small fall in MAP in normal subjects
| large fall in MAP in hypertensive patients (since in these patients renin secretion is usually enhanced)
108
what are the common adverse effects of ACE inhibitors?
```
initial hypotention (esp in patients on diuretics too)
dry cough (due to bradykinin accumulation)
renal dysfunction
```
109
what are the adverse effects of ACE inhibitors?
```
initial hypotention (esp in patients on diuretics too)
dry cough (due to bradykinin accumulation)
```
110
what is the role of AT1 receptor blockers (ARBs)?
| -sartan
competitevly block the agonist action of angeiotensin I at AT1 receptors
111
what are ACEIs and ARBs contraindicated in?
pregnancy
| bilateral renal artery stenosis
112
if a patient has a intolerable dry cough with ACE inhibitors what drug should they be switched to?
ARBs
| as there is no increase in bradykinin
113
what are ACEIs and ARBs contraindicated in?
pregnancy
| bilateral renal artery stnosis
114
what are the clinical uses of ACE inhibitors and ARBs? (and explain)
1. hypertension (reduces TRP and MABP)
2. cardiac failure (reduces TPR to decrease cardiac work load, also causes regression of LVH)
3. following an MI (same as above)
115
what are the clinical uses of beta-blockers?
1. angina (only stable and unstable)
because the decrease myocardial O2 requirement and increase the amount of time spent in diastole which improves perfusion
2. hypertenstion
reduce MAP and reduced renin release from the kidneys
3. heart failure
decreases cardiac work load
116
what is the function of calcium antagonists?
prevent the opening of L-type channels in response to depolarisation, this limits calcium influx
117
in the SA node what do calcium antagonists do?
reduce heart rate by reducing rate of upstroke of the AP
118
in the AV node what do calcium antagonists do?
reduce rate of conduction
119
in the ventricles what do calcium antagonists do?
reduce force of contraction by reducing Ca in plateau phase
120
what are the 3 main calcium antagonists?
verapamil (cardiac selective)
amlodipine (smooth muscle selective)
diltiazem
121
what are calcium antagonists clinically used in?
hypertension (reduce TPR and MAP)
angina (coronary vasodilation)
dysrhthmias (supression of AV conduction)
122
which calcium antagonists are preferred for hypertension and why?
smooth muscle selective
| to minimise unwanted effects on cardiac muscle (important in heart failure or heart block)
123
what is the length of acting for amlodopine?
long acting
124
what calcium antagonists is used in dysrhthmias?
verapamil
125
what drug combination should be completely avoided in heart failure?
beta-blockers and verapamil
126
why do calcium antagonists work in variant angina? (unlike beta blockers)
variant angina is caused by episodic coronary spasms, so calcium antagonists work well by not allowing the cell to obtain the calcium required for a spasm
127
what are minoxidil and nicorandil?
potassium channel openers
128
how do potassium channel openers work?
work on vascular smooth muscle to open calcium-dependent K channels. this causes hyperpolarisation which switches off L-type calcium channels- causing relaxation of vascular smooth muscle
129
what is nicorandil used in?
angina
| not used too commonly
130
what is minoxidil used in?
hypertension (but only as a last resort)
131
what are the negative effects of minoxidil?
```
reflex tachycardia (prevented by a beta-blocker)
salt and water retention (alleviated by a diuretic)
```
132
what are prazosin and doxazosin?
a1-adrenoceptor antagonists
133
what is the dunction of a1-adrenoceptor antagonists?
cause vasodilation by blocking sympathetic/hormonal effect on a1-adrenoceptors
134
what is the clinical use a1-adrenoceptor antagonists?
hypertension (especially if patient has prostatic hyperplasia)
135
what is the function of diuretics?
act on kidneys to increase the excretion of Na, Cl and H20
136
where do thiazide diuretics inhibit NaCl reabsorption?
distal tubule
137
where do loop diuretics inhibit NaCl reabsorption?``
ascending limb of hte loop of Henle
138
what is the main adverse affect of using thiazide or loop diuretics?
loss of K+
139
how is the loss of K+ due to thiazide or loop diuretics corrected?
co-administration of a potassium sparring diuretic
| k+ supplements
140
what are the clinical uses of thiazide diuretics? (eg bendroflumethiazide)
mild heart failure
| hypertension
141
what are the clinical uses of loop diuretics?
acute pulmonary oedema
| chronic heart failure
142
name 6 classes of anti-hypertensive drugs?
```
calcium antagonists
ACE inhibitors
ARBs
alpha blockers
beta blockers
thiazide diuretics
```
143
name 4 classes of anti-anginal drugs?
nitrates
beta blockers
calcium antagonists
nicorandil
144
name 3 classes of antithrombotic drugs?
antiplatelets (against platelets)
anticoagulants (against clotting factors)
fibrinolytics (dissolve preformed clots)
145
name 2 classes of anticholesterol drugs?
statins
| fibrates
146
what is bendroflumethiazide?
thiazide diuretic
147
what is furosemide?
a loop diuretic
148
what are the 4 side effects of diuretics?
1. hypokalaemia (tiredness, arrhythmias)
2. hyperglycaemia (diabetes)
3. hyperuricaemia (gout)
4. impotence
149
what are cardioselective b-blockers used in?
| eg atenolol
angina
hypertension
heart failure
150
what are non-selective b-blockers used in?
| eg propanolol
thyrotoxicosis
151
what type of patients are beta blockers contraindicated in?
asthmatic patients
| patients with reynaulds
152
what are the effects of beta blockers in short term heart failure vs long term heart failure?
beta blockers can worsen heart failure in short term
| improve heart failure in long term
153
what are the 2 types of calcium antagonists?
dihydropyridines eg amlodipine
| rate-limiting calcium antagonists eg verapamil, diltiazem
154
what can be the adverse result of giving beta blockers and rate-limiting calcium antagonists together?
full heart block
155
what type of arrhythmias are rate-limiting calcium antagonists useful in treating?
superventricular arrthymias (AF, SVT)
156
what is the main side effect of alpha blockers?
postural hypotension
157
what is a rare, life threatening adverse reaction of ACE inhibitors?
angioneurotic oedema
| never give to a patient with previous angioneurotic oedema
158
why should you avoid giving ACEI to women of childbearing ages?
they might not know they are pregnant yet, contraindicated in pregnancy
159
what type of drugs can pregnant women use to control pregnancy-induced hypertension?
calcium inhibitors and beta blockers
160
what type of heart failure can nitrates be used in?
acute heart failure not chronic
161
what is the function of antiplatelet agents?
prevent new thrombosis
| dont break down clots that have already formed
162
when are antiplatelet agents used?
angina
acute MI
CVA/TIA
(patients at risk of MI/CVS)
163
what are the 3 main side effects of antiplatelet agents?
```
haemorrhage
peptic ulcer (leading to haemorrhage)
aspirin sensitivity (asthma)
```
164
what is the function of anticoagulants?
prevent new thrombosis
165
how is heparin administered?
IV
166
how is warfarin administered?
oral
167
what clotting factors does warfarin block?
2, 7, 9, 10
168
what is warfarin used in?
DVT
PE
NSTEMI
AF
169
what are the side effects of anticoagulants?
haemorrhage
170
how do you control the dose of warfarin?
using INR
171
how do you reverse an overdose of warfrin? (ie if there is a haemorrhage)
vitamin K
172
what clotting factor does rivaroxaban inhibit?
10a
173
what clotting factor does dabigatran inhibit?
2a
174
what does clotting factor Xa do?
convert prothrombin (II) into thrombin (IIa)
175
name 2 fibrinolytic drugs?
streptokinase
| tPA
176
when are fibrinolytic drugs used?
STEMI
PE
CVA
(Selected cases only)
177
what is the adverse side effect of fibrinolytic drugs?
haemorrhage
178
when must you avoid using fibrinolytic drugs?
```
recent haemorrhage
trauma
bleeding tendencies (eg haemophilla)
severe diabetic retinopathy
peptic ulcer
```
179
how do statins work?
block HMG CoA reductase
180
when are statins used?
```
hypercholesterolaemia
diabetes
angina/MI
CVA/TIA
(high risk of MI/CVA)
```
181
what are the possible side effects of statins?
myopathy (muscle ache)
| rhabdomyolysis renal failure (renal muscle break down)
182
when are fibrates used?
hypertriglyceridaemia
| low HDL cholesterol
183
what 2 drugs are anti-arrhythmic drugs?
```
amiodarone
flecainide
(calcium antagonist
beta blockers
digoxin can also be used in SVAs but arent technically anti-arrhythmic drugs)
```
184
what drug do you use in the acute phase of an SVT?
adenosine
185
what are the 3 side effects of anti-arrhythmic drugs?
photoxicity
pulmonary fibrosis
thyroid abnormalities
186
what are the 2 main effects of digoxin?
1. degree of AV node block
| 2. increased ventricular contraction
187
what are the side effects of digoxin?
```
bradycardia and heart block
ventricular arrhythmias (fatal)
nausea
vomitting
yellow vision
```
188
how are non-polar lipids transported in the blood?
within lipoproteins
189
what ratio of LDL:HDL is strongly associated with cardiovascular disease? (atherosclerosis)
high LDL
| low HDL
190
what are the 2 main sections of an lipoprotein?
hydrophobic core
| hydrophilic coat
191
what does the hydrophobic core of the lipoprotein contain?
esterified cholesterol and triglycerides
192
what does the hydrophilic coat of the lipoprotein contatin?
a monolayer of amphipathic cholesterol, phospholipids and one or more apoprotein
193
what are the 4 main lipoproteins?
HDL
LDL
VLDL
chylomicrons
194
what is the biggest lipoprotein in terms of diameter?
chylomicrons
195
cholesterol within the hydrophilic coat of the lipoprotein are amphipathic. where does the hydrophobic part face and where does the hydrophilic part face?
hydrophobic part of cholesterol face into the centre of the sphere
hydrophilic part of the cholesterol face the aqeuous component of the blood
196
what apoproteins are associated with HDL?
apoA1
| apoA2
197
what apoproteins are associated with LDL?
apoB-100
198
what apoproteins are associated with VLDL?
apoB-100
199
what apoproteins are associated with chyomicrons?
apoB-48
200
what are apoproteins?
markers which say if the lipoprotein is LDL or HDL
201
what is familial hypercholesterolaemia?
a genetic condition in which the patient is unable to clear LDL from the blood due to lack of LDL receptors on hepatocytes
202
what type of lipoproteins deliver triglycerides to muscle (for ATP) and adipocytes (for storage)?
apoB -containing lipoproteins
203
where are chylomicrons formed?
intestinal cells
204
what is the function of chylomicrons?
transport dietary triglycerides to muscle and adipocytes
| exogenous pathway
205
what is the 3 phase life cycle of an ApoB-containing lipoprotein?
1. assembly
2. intravascular metabolism
3. receptor mediated clearance
206
where does assembly of an ApoB-containing lipoprotein occur?
apoB100-containing lipoproteins: liver
| apoB46-containing lipoproteins: intestine
207
what does intravascular metabolism of an apoB-containing lipoprotein involve?
hydrolysis fo the triglyceride core
208
what does receptor mediated clearance of an apoB-containing lipoprotein involve?
lipoprotein attaches to a receptor and is endocytsosed into the cell and removed
209
what needs to happen to the triglyceride to be absorbed in the intestine?
broken down into monoglyceride and free fatty acids
210
after absorption in the intestine what happens to the monoglyceride and free fatty acids?
triglyceride is resynthesised from them
211
how is cholesterol absorbed by an enterocyte?
a transport protein:
| NPC1L1
212
where within the enterocyte is apoB-48 made?
ribosome
213
once the triglycerides have reformed in the enterocyte what happens?
1. they form a droplet with apoB48 incorporated inside
2. lipidation occurs
3. cholesteryl esters are added
4. particle (now called a chylomicron) leave by exocytosis
214
where do chylomicrons go once having left the enterocyte?
lymphatic syste,
215
where are VLDL particles assembled?
in liver hepatocytes
216
what are VLDL partcles (containing triglycerides) assembled from?
from free fatty acids derived from adipose tissue and de novo synthesis
217
to target triglyceride delivery to adipose and muscle tissue, chylomicrons and VLDL particles must become activated. How does this occur?
activation of chylomicrons and VLDL occurs by the transfer of apoCII from HDL particles
(apo C2)
218
what does apoCII facilitate once transfered to the VLDL or chylomicron?
binding of chylomicrons and VLDL particles to lipoprotein lipase (LPL)
219
what is lipoprotein lipase? (LPL)
a lipolytic enzyme associated with the endothelium of capillaries in adipose and muscle tissue
220
what does lipoprotein lipase (LPL) do?
LPL hydrolyses the lipoprotein core triglycerides to free fatty acids and glycerol which enter tissues
221
what are chylomicron and VLDL remnants?
lipoprotein particles depleted of triglycerides (due to the action of LPL) but still containing cholesteryl esters
222
once LPL has enriched the chylomicrons and VLDL with cholesterol ester by removing triglyceride what happens?
chylomicrons and VLDL dissociate from LPL and apoCII is transferred back to HDL particles in exchange for apoE
223
apoE causes the remnants to return where?
to the liver
224
once in the liver what happens to the VLDL and chylomicron particles?
further metabolised by hepatic lipase and then all apoB48-containing remnants and 50% of apoB100 containing-remnants are cleared by receptor-mediated endocytosis into hepatocytes
225
what happens to the remaining 50% of apoB100-containg remnants which havent been taken into the hepatocytes?
they loose further triglycerides through hepatic lipase, so become smalle and more enriched in cholester ester and eventually beome LDL particle
(only have apoB100 now, lost apoE)
226
during triglyceride metabolism by hepatic lipase of the remaining apoB100-containing remnants, what particle forms first before the LDL forms?
IDL
227
what is clearance of LDL particles dependent upon?
expression of the LDL receptor expressed by the liver (and other tissues)
228
how do hepatocytes uptake the LDL particles?
receptor-mediated endocytosis
229
once the LDL has been taken up by the hepatocyte, how is cholesterol released from the cholesterol ester?
hydrolysis
230
what 3 things does the cholesterol released from the LDL cause?
1. inhibition of HMG CoA reductase
2. down regulation of LDL receptor expression
3. storage of cholesterol as cholesterol ester
231
what is HMG-CoA reductase?
the rate limiting enzyme in de novo cholesterol synthesis
232
what does inhibition of HMG-CoA cause?
suppression of de novo endogenous cholesterol synthesis
233
when an endothelium lining is damaged, what is it able to do?
uptake LDL from blood into the intima of the artery
234
when LDL is within the intima of the artery what occurs?
oxidation to OXLDL
| arthrogenic oxidised LDL
235
why do monocytes migrate to the intima of the damaged endothelium?
(where they become macrophages)
to try mop up the cellular debris
236
what do macrophages turn into when they take up the OXLDL in the damaged endothelium?
foam cells that form a fatty streak
237
what starts to lay down on top of this fatty streak?
smooth muscle cells and collagen
238
what makes up an atheromatous plaque?
lipid core (Dead foam cells) and a fibrous cap (smooth muscle and connective tissue)
239
what is the role of HDL?
transports excess cholesterol from cells to liver
| reverse cholesterol transport
240
how is cholesterol removed from the body?
synthesised to make bile salts or secreted in bile
241
what are the 2 mechanisms of reverse cholesterol transport?
1. HDL reaching liver interacts with receptor that allows transfer of cholesterol and cholestryl esters into hepatocytes
2. in plasma, cholesterol ester transfer protein (CETP) mediates transfer of cholesterol esters from HDL to VLDL and LDL (indirectly returning cholesterol to the liver)
242
what is secondary dislipidaemia?
lipidaemia as a consequence of another disease
| eg type 2 diabetes, hypothyroidism, alcoholism, liver disease
243
by competitively inhibiting HMG CoA reductase, what effect to statins have?
decrease in hepatocyte cholesterol synthesis causes a decreased cholesterol concentration in the hepatocyte which results in a compensatory increased LDL receptor expression and enhanced LDL clearance
244
why are statins ineffective in familial hypercholesterolaemia?
LDL receptors are lacking, so increased clearance of LDL doesnt occur
245
when and how are statins administered?
orally at night
246
what is the first line drug for patients with very high triglycride levels?
fibrates
247
how to fibrates work?
act as agonists of a nuclear receptor (PPARalpha) to enhance the transcription of LPL
248
what type of patients should you avoid giving fibrates in and why?
alcoholics
| because even though they are predisposed to hypertriglyceridaemia they are also exposed to rhabdomyolosis
249
what type of drug are colestyramine, colestipol and colsevelam?
bile acid binding resins
250
what is the function of bile acid binding resins?
interrupt enterohepatic recycling of cholesterol
non-absorbable so cause the excretion of bile salts thus resulting in more cholesterol to be converted to bile salrs
251
what 2 main effects do bile acid binding resins have?
1. decreased absorption of bile salts and triglycerides
| 2. increased LDL receptor expression
252
what is the adverse effect of bile acid binding resins?
GI irritation
253
how does ezetimibe work?
inhibits NPC1L1 to reduce cholesterol absorption
254
when is ezetimibe contraindicated?
breast-feeding females
255
in what type of heart condition should calcium antagonists not be used?
heart failure
| they make it worse as they are negative inotropes
256
what is the process of haemostasis?
preventing blood loss from a damaged vessel
257
what are the 3 features of haemostasis?
1. local vasoconstriction
2. adhesion and activation of platelets at site of injury
3. formation of fibrin (a insoluble mesh)
258
what is type of haemostasis is thrombosis?
pathological
259
what is thrombosis?
a haemotological plug formed in the absence of bleeding
260
what are the predisposing factors to thrombus formation?
virchows triad:
1. injury to vessel wall
2. abnormal blood flow.
3. increased coaguablity of the blood
261
what is an arterial thrombus?
a white thrombus made of mainly platelets in a fibrin mesh
262
what is a venous thrombus?
a red thrombus rich in red blood cells and fibrin. has a white head and a jelly-like red tail
263
compare the sites of an embolism formed from an arterial thrombus and a venous thrombus?
embolism from an arterial thrombus lodges in an artery in the systemic circulation
embolism from a venous thrombus lodges in an artery in the pulmonary circulation
264
what is the main event in blood coagulation?
fibrinogen (a soluble agent) turning into fibrin (an insoluble agent)
265
what activated clotting factor converts fibrinogen to fibrin?
thrombin (IIa)
266
how are clotting factors activated?
proteolytic cleavage
267
what activated clotting factor activates prothrombin? (II)
Xa
268
how is factor X activated?
in vivo pathway or contact pathway
269
what are the contact pathway factors?
XIa and XIIa
270
what are the in vivo pathway factors?
tissue factor and VIIa
271
what activates the in vivo pathway or contact pathway which ultimately ends up in fibrin formation?
endothelial damage
272
upon activation of plateltes what aggregation factors do they release?
preformed (ADP, 5-HT)
| synthesised on demand (TXA2)
273
what do platelets do to help the coagulation cascade?
provide surfaces which bring clotting factors together
274
before a clotting factor can attach to the negative phospholipids on the platelet surface what must occur?
gamma- carboxylation of glutamate residues of the cloting factor
(clotting factors are still inactive at this point)
275
what co-factor does the carboxylase enzyme that mediates gamma-carboxylation of the glutamate residues of clotting factors require?
vitamin K (in it's reduced form)
276
what happens to the reduced vitamin K co-factor in the process of gamma-carboxylation of the glutamate residues of clotting factors?
becomes oxidised
| forms oxidised vitamin K
277
what is the job of vitamin K reductase?
converts oxidised vitamin K back into reduced vitamin K
278
what enzyme does warfarin block?
| and what is the result?
blocks vitamin K reductase
prevents formation of reduced vitamin K and therefore gamma-carboxylation of the glutamate residues of clotting factors can't occur and the coagulationg pathway is interrupted
279
what type of thrombosis are anticoagulants used in the prevention and treatment of?
venous thromosis
280
what are 4 uses of warfarin?
DVT
prevention of post-operative thrombosis
patients with artificial heart valves
atrial fibrillation
281
what is the name of the reduced form of vitamin K?
hydroquinone
282
what is the name of the oxidised form of vitamin K?
epoxide
283
what factors does warfarin render inactive?
II, VII, IX, X
284
describe the onset/duration of warfarin?
slow onset, long half life (40 hrs)
285
what type of therapeutic index does warfarin have?
low therapeutic index
286
what are the 3 main factors that potentiate warfarin action and so increase risk of haemrrhage?
liver disease
high metabolic rate
drug interactions
287
why might liver disease potentiate warfarin?
decreased clotting factors
288
why might high metabolic rate potentiate warfarin?
increased clearance of clotting factors
289
what 3 types of drug interactions might potentiate warfarin?
1. agents that inhibit hepatic metabolism of warfarin
2. agents that inhibit platelet function (eg some NSAIDS)
3. agents that inhibit decrease availability of vitamin K
290
what are the 3 main factors which might lessen warfarin action? (risk of thrombosis increased)
1. physiological state
2. vitamin K consuption
3. drugs interactions
291
what types of physiological states may lessen warfarin action and increase risk of thrombosis?
hypercoaguable states
| low metabolic states (decreased degradation of clotting factors)
292
what is antithrombin III? (AT III)
clotting factor inhibitor
| binds to clotting factors rendering them inactive
293
how does heparin work?
binds to antithrombin III and increases its affinity for clotting factors (particularly Xa and IIa) to increase their rate of inactivation
294
compare heparins effect on Xa and IIa
heparin must bind to both AT III and IIa to inhibit IIa
| heparin only needs to bind to AT III to inhibit Xa
295
what factors do LMWHs inhibit?
Xa
(cant inhibit IIa because they cant bind to both AT III and IIa at the same time, for Xa they only need to bind to AT III)
296
what is the order of elimination of herparin?
zero order kinetics
297
what is the order of elimination of LMWHs?
first order kinetics
298
why is heparin preferred to LMWH in renal failure?
LMWH is excreted by renal ecretion
299
why should the inibility of LMWH to inhibit factor IIa not be important?
because it inhibits factor Xa which is upstream to IIa, so should indirectly inhibit IIa
300
what are the 4 adverse affects of heparin gnd LMWHs?
haemorrhage
osteoporosis (long term)
hypoaldosteronism
hypersensitivity reactions
301
what is the treatment for a patient on heparin or LMWH wo gets a haemorrhage?
discontiunue the heparin or LMWH
| administer protamine sulfate (inactivated heparin)
302
what is the benefit of dabigatran and rivaroxaban over heparin and LMWHs?
orally active agents
(no need for IV)
less haemorhage risk
303
what factor does dabigatran inhibit?
IIa (thrombin)
304
what factor does rivaroxaban inhibit?
Xa
305
when are rivaroxaban and dabigatran used clinically?
to prevent venous thrombosis in patients undergoing hip and knee replacements
306
what is the function of von willebrand factor?
allows platelets to adhere to endothelium
307
what do ADP, 5HT and TXA2 do?
act on the cell surface receptor of platelets to cause aggregation and cross linking via fibrinogen
308
what enzyme does aspirin block irreversibly?
| and what effect does this have?
cyclo-oxygenase 1
(COX 1)
in platelets: prevents the synthesis of thromboxane A2 (TXA2) and so prevents stimulation of aggregation and cross-linking (adhesion)
309
what does clopidogrel block irreversibly?
P2Y(12) receptor on platelets
| prevents ADP binding to receptor and stimulation of aggregation and cross-linking (adhesion)
310
what does tirofiban block?
GPIIb/IIa receptor on platelt to prevent the cross-linking by fibrinogen
311
what type of thrombosis are anti-platelet drugs used in?
arterial thrombosis
312
how and why is tirofiban administered?
IV in short term treatment to prevent MI in high risk patients with unstable angina
(with aspirin and heparin)
313
describe the fibrinolytic cascade?
opposes coagulation cascade
| plasminogen is converted to plasmin which breaks down the fibrin into fibrin fragments causing clot lysis
314
what type of agents up regulated the conversion of plasminogen to plasmin?
fibrinolytic agents eg tPA, strptokinase
315
how are fibrinolytic drugs administered?
IV
| within as short a period as possible of the event
316
what are fibinolytics used for clinically?
reopen occluded arteries eg MI or stroke
| less freq: reopen life-threatening venous thrombosis or PE
317
why are fibrinolytics not given to every patient who has had an acute MI?
because PCI is superior if aviable promptly
318
why is action of streptokinase blocked after 4 days?
generation of antibodies
319
to what patients should you not give streptokinase?
to patients with recent streptococcal infections
320
how are tPAs administered?
IV (because of short half life)
